The present invention relates to selective 4-(phenyl or pyridyl)imidazole derivative neuropeptide Y Y5 receptor antagonists useful in the treatment of eating disorders, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds.
Neuropeptide Y is a 36 amino acid peptide that is widely distributed in the central and peripheral nervous systems. This peptide mediates a number of physiological effects through its various receptor subtypes. Studies in animals have shown that neuropeptide Y is a powerful stimulus of food intake, and it has been demonstrated that activation of neuropeptide Y Y5 receptors results in hyperphagia and decreased thermogenesis. Therefore compounds that antagonize neuropeptide Y at the Y5 receptor subtype represent an approach to the treatment of eating disorders such as obesity and hyperphagia, and diabetes.
Substituted imidazoles are used in various pharmaceutical and non-pharmaceutical applications. WO 99/01128 discloses substituted diarylimidazoles as NPY Y5 receptor antagonists.
The present invention relates to compounds represented by the structural formula I: 
or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein
X is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94;
Y is 1 to 3 substituents independently selected from the group consisting of H, halogen, trihaloalkyl, C1-C6 alkyl, C1-C6 alkenyl, C3-C7-cycloalkyl, C1-C6 alkyl substituted by C3-C7-cycloalkyl, xe2x80x94OH, xe2x80x94O(C1-C6)alkyl, xe2x80x94SH, xe2x80x94S(C1-C6)alkyl, or xe2x80x94CN.
R is R1-phenyl, R1-pyridyl, adamantyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(R9-phenyl), xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(R9-phenyl), xe2x80x94CF3, C1-C6alkyl, C3-C7-cycloalkyl, or heterocycloalkyl selected from the group consisting of 4 to 6 membered rings comprising 3 to 5 carbon ring members and 1 to 3 ring members selected from the group consisting of xe2x80x94NR8xe2x80x94, xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94, heterocycloalkyl(C1-C6)alkyl wherein heterocycloalkyl is as defined above, heteroaryl(C1-C6)alkyl, 
xe2x80x83provided that when R is R1-phenyl, R1-pyridyl, adamantyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(R9-phenyl, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(R9-phenyl), xe2x80x94CF3, C1-C6alkyl, or C3-C7-cycloalkyl, Y is 3-CF3;
n is 0, 1, 2 or 3;
R1 is 1-3 substituents independently selected from the group consisting of hydroxy(C1-C6)alkyl; NO2; xe2x80x94CHO, xe2x80x94C(O)O(C1-C6)alkyl; xe2x80x94C(O)NR4R5; xe2x80x94(CH2)pNR4R5; xe2x80x94(CH2)pNR4R6; xe2x80x94NR4SO2R7; xe2x80x94NHCOH; xe2x80x94NR4COR5; xe2x80x94NHC(O)NR4R5; aryl; and heteroaryl;
p is 0, 1, 2 or 3;
R4 is hydrogen or C1-C6 alkyl;
R5 is C1-C6 alkyl, aryl or heteroaryl; provided R4 and R5 are not both C1-C6 alkyl, and provided that when R4 is hydrogen, R5 is not C1-C6 alkyl; or R4 and R5 together are C3-C6 alkylene and together with the nitrogen to which they are attached form a 4-7 membered ring; or R4 and R5, together with the nitrogen to which they are attached, form a 5, 6 or 7-membered ring, wherein 1 or 2 ring members are independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NR12xe2x80x94;
R6 is C3-C7 cycloalkyl, benzyl, diphenylmethyl or 
xe2x80x83or R4 and R6, together with the nitrogen to which they are attached form a group of the formula 
R7 is C1-C6 alkyl, C3-C7 cycloalkyl, benzyl, aryl, or heteroaryl;
R8 is hydrogen, C1-C6 alkyl, xe2x80x94C(O)xe2x80x94(C1-C6 alkyl), xe2x80x94C(O)xe2x80x94(C3-C7 cycloalkyl), xe2x80x94C(O)-aryl, xe2x80x94C(O)-heteroaryl, xe2x80x94SO2xe2x80x94R7, aryl, heteroaryl, xe2x80x94CONR4R5 or xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C6)alkyl;
R9 is 1 to 3 substituents independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogeno and xe2x80x94CF3;
R10 and R11 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R10 and R11, together with the carbon to which they are attached, form a C3-C7 ring; and
R12 is hydrogen, C1-C6 alkyl, xe2x80x94C(O)xe2x80x94(C1-C6 alkyl), xe2x80x94SO2xe2x80x94R7, R9-phenyl, xe2x80x94CONR4R5, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94CHO, C3-C7 cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, benzyl, benzoyl, xe2x80x94C(O)(C3-C7)cycloalkyl, xe2x80x94C(O)(C1-C6)alkylphenyl, pyridylmethyl, xe2x80x94C(O)pyridyl, xe2x80x94C(O)N(di-(C1-C6)-alkyl) or 4-tetrahydropyranyl.
One group of preferred compounds is that wherein R is as defined above; R1 is 1-3 substituents selected from the group consisting of hydroxy(C1-C6)alkyl, NO2, xe2x80x94CHO, xe2x80x94C(O)O(C1-C6)alkyl, xe2x80x94(CH2)pNR4R5, xe2x80x94(CH2)pNR4R6, xe2x80x94NR4SO2R7, xe2x80x94NHCOH, xe2x80x94NHCOR5, xe2x80x94NR4COR5xe2x80x94, NHC(O)NR4R5, aryl and heteroaryl; and p is 0, 1 or 2.
Another group of preferred compounds is that wherein R is adamantyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(R9-phenyl), xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(R9-phenyl), xe2x80x94CF3, C1-C6 alkyl, C3-C7-cycloalkyl, heteroaryl-(C1-C6)alkyl, heterocycloalkyl-(C1-C6)alkyl, or 
Another group of preferred compounds is that wherein R is heterocycloalkyl, 
wherein heterocycloalkyl is defined as 
and R8 is preferably C(O)xe2x80x94(C1-C6 alkyl), xe2x80x94C(O)xe2x80x94(C3-C7 cycloalkyl), xe2x80x94C(O)-aryl, xe2x80x94C(O)-heteroaryl, xe2x80x94SO2xe2x80x94R7, aryl, heteroaryl, and xe2x80x94CONR4R5.
In another group of preferred compounds of formula I, R is R1-phenyl or R1-pyridyl of the formula 
R1 is preferably xe2x80x94NR4SO2R7, wherein R4 is H or straight or branched C1-C6 alkyl, and R7 is straight or branched C1-C6 alkyl.
Preferred compounds of this invention include those of formula I wherein X is xe2x95x90CHxe2x80x94, Y is 3-CF3, and R is selected from the group consisting of: 
Another group of preferred compounds of this invention include those of formula 1 wherein X is xe2x95x90CHxe2x80x94, and R is selected from the group consisting of: 
Still another group of preferred compounds of this invention include those selected from the group consisting of: 
Yet one more group of preferred compounds of this invention include those selected from the group consisting of: 
The present invention also relates to a method of treating eating disorders, such as obesity and hyperphagia, and diabetes comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I.
Another aspect of the invention is a pharmaceutical composition for treating eating disorders and diabetes which comprises a compound of formula I in combination with a pharmaceutically acceptable carrier.
Except where stated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of xe2x80x9calkylxe2x80x9d applies to xe2x80x9calkylxe2x80x9d as well as the xe2x80x9calkylxe2x80x9d portions of xe2x80x9calkoxyxe2x80x9d, etc.
Alkyl represents a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. If the number of carbon atoms is not specified, e.g., if the term lower alkyl is used, chain lengths of 1 to 6 carbons are intended.
Aryl-(including the aryl portion of arylalkyl and heteroarylalkyl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted with one or more (e.g., 1 to 3) of halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, xe2x80x94C(O)N(R18)2, xe2x80x94SO2R18, xe2x80x94SO2N(R18)2, amino, alkylamino, dialkylamino, xe2x80x94COOR23 or xe2x80x94NO2, wherein R18 represents H, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl and R23 represents alkyl or aryl;
Cycloalkyl represents a saturated carbocyclic ring having 3 to 7 carbon atoms.
Halogeno represents fluoro, chloro, bromo or iodo.
As defined above, heterocycloalkyl represents 4 to 6 membered rings comprising 3 to 5 carbon ring members and 1 to 3 ring members selected from the group consisting of xe2x80x94NR12xe2x80x94, xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94. Where a heterocycloalkyl ring comprises more than one heteroatom, no rings are formed where there are adjacent oxygen atoms, adjacent sulfur atoms, or three consecutive heteroatoms. Examples of heterocycloalkyl rings are piperazinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl and thiomorpholinyl.
Heteroaryl means a 5 or 6-membered aromatic ring comprising 1 to 3 heteroatoms independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94Nxe2x95x90, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of heteroaryl groups are pyridyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl. The heteroaryl rings are attached to the rest of the molecule through a ring carbon atom. All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. The substituted heteroaryl groups specifically identified in the definition of R, e.g. R2-pyridyl and R3-thiazolyl, can be substituted at any available ring carbon atom.
When a variable appears more than once in the structural formula, for example R1, the identity of each variable appearing more than once may be independently selected from the definition for that variable.
Compounds of the invention are tautomeric with respect to the 4- and 5-positions of the imidazoyl ring, i.e., the following structural formulae are equivalent: 
N-oxides can form on a tertiary nitrogen present in an R substituent (e.g., R is 3-pyridyl N-oxide) or when X is xe2x95x90Nxe2x80x94, in the Y substituted ring.
Compounds of formula I can exist in unsolvated and solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of this invention.
A compound of formula I may form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.
Compounds of formula I may be produced by processes known to those skilled in the art as shown in the following reaction schemes and in the preparations and examples below.
Scheme 1
Compounds of formula 1a or 1b wherein X is xe2x80x94CHxe2x95x90 and R is R1-phenyl or R1-pyridyl, respectively, can be prepared by the following procedure wherein the imidazolyl ring is formed during the reaction: 
CF3-substituted acetophenone is brominated, then reacted with a phenyl- or pyridyl-substituted amidine to obtain compounds of formula 1a or 1b. Compounds prepared by this method can be converted to other compounds of formula I by treating the R1 substituent using methods well known in the art to obtain other R1 substituents, e.g., an ester can be converted to an acid, an acid can be condensed with an amine, a nitro group can be reduced to an amine, and an amine can be sulfonated. When necessary, the NH moiety of the imidazolyl ring is protected with a group such as (2-trimethylsilyl)ethoxymethyl prior to reaction.
Scheme 2
Compounds of formula 1c wherein X is xe2x95x90CHxe2x80x94 can be prepared by reacting an N-protected (CF3-phenyl)-substituted imidazole of formula II with an R-containing reagent, for example an R-boronic-acid of formula III, followed by deprotection of the resultant intermediate of formula IV, as shown in the following typical reaction scheme, wherein SEM is (2-trimethylsilyl)ethoxymethyl: 
Scheme 3
Compounds of formula 1d wherein R is a substituted 1,2,5,6-tetrahydropyridyl of the formula 
can be prepared by reacting an N-protected (CF3-phenyl)-substituted imidazole with an N-protected 4-piperidone, followed by dehydration of the resultant intermediate of formula VII, as shown in the following typical reaction scheme wherein R8 is xe2x80x94SO2xe2x80x94R7: 
Alternatively, compounds of formula 1d wherein X is xe2x95x90CHxe2x80x94 can be prepared by reacting an N-protected (CF3-phenyl)-substituted imidazole with an N-protected 4-(trifluoromethanesulfonyloxy)-1,2,5,6-tetrahydropyridine of formula VIII, followed by deprotection of the resultant intermediate of formula IX. 
Compounds of formula 1d can be converted to compounds of formula I wherein R is N-substituted-4-piperidyl by reducing the compound of formula 1d, for example by hydrogenation.
Scheme 4
Compounds of formula 1e wherein R is an N-R8-substituted piperidinylmethyl can be prepared by reacting an N-protected (CF3-phenyl)-substituted imidazole of formula II with an N-protected 4-methylenepiperidine. After deprotection of the piperidinyl moiety of the resultant intermediate of formula X, using procedures well known in the art, the piperidyl nitrogen on the intermediate of formula XI is substituted with R8 and the protecting group on the imidazolyl nitrogen is removed: 
Scheme 5
A method of preparation of compounds of formula 1f wherein R is N-substituted-4-piperidyl is by reacting a 5- (or 4-)-bromo-2-(N-protected-4-piperidyl)imidazole of formula XII with an aryl boronic acid of formula XIII. After deprotection of the piperidinyl moiety of the resultant intermediate, using procedures well known in the art, the piperidyl nitrogen on the intermediate of formula XIV is substituted with R8 and the protecting group on the imidazole nitrogen is removed. 
Scheme 6
Compounds of formula 1g wherein R is a substituted piperazinyl of the formula 
can be prepared by reacting an N-protected phenyl-substituted imidazole with piperazine. Derivitization of the resultant intermediate of formula XV is followed by deprotection of the imidazole nitrogen by methods known to those skilled in the art to give compounds of fourmula 1g where R8 is aryl, heteroaryl, or R7xe2x80x94SO2xe2x80x94. Alternatively, the imidazole nitrogen of intermediate XV is deprotected, and the piperazine nitrogen of the resultant intermediate is reacted with an isocyanate or an acyl chloride to give compounds of formula 1g where R8 is xe2x80x94CONR4R5, xe2x80x94COxe2x80x94(C1-C6)-alkyl, xe2x80x94CO(C3-C7)cycloalkyl, xe2x80x94C(O)aryl, C(O)heteroaryl. 
Starting materials of formula II are prepared according to the following reaction scheme: 
xcex1-Bromo-(3-trifluoromethyl)acetophenone is condensed with formamide and a (2-trimethylsilyl)ethoxymethyl group is placed on the imidazole nitrogen. The 2-position of the imidazolyl group is iodinated to obtain the starting material of formula II.
Starting material of formula XII is prepared according to the following scheme; 
Isonipecotic acid is condensed with aminoacetaldehyde dimethyl acetal and the product is reacted with ammonium acetate to form an imidazole substituted at the 2-position by N-protected 4-piperidinyl. A (2-trimethylsilyl)ethoxyoxymethyl group is placed on the imidazole nitrogen and the resultant product is brominated to give a mixture of regioisomeric 4- and 5-bromoimidazoles of formula XII.
The pyridyl amidine shown in Scheme 1 is prepared by treating 3-cyanopyridine with an ammonia equivalent such as LHMDS or methylchloroaluminum amide.
Substituted amidines used in the method of Scheme 1 are known or can be prepared by known procedures.
The compounds of formula I exhibit selective neuropeptide Y Y5 antagonizing activity, which has been correlated with pharmaceutical activity for treating eating disorders, such as obesity and hyperphagia, and diabetes.
The compounds of formula I display pharmacological activity in test procedures designated to indicate neuropeptide Y Y5 receptor antagonist activity. The compounds are non-toxic at pharmaceutically therapeutic doses. Following are descriptions of the test procedures.
CHO cells expressing NPY Y5 receptors were maintained in Ham""s F-12 media (Gibco-BRL) supplemented with 10% FCS (ICN), 1% penicillin-streptomycin, 1% non-essential amino acids and 200 xcexcg/ml Geneticin (GibcoBRL #11811-031) under a humidified 5% CO2 atmosphere. Two days prior to assay, cells were released from T-175 tissue culture flasks using cell dissociation solution (1xc3x97; non-enzymatic [Sigma #C-5914]) and seeded into 96-well, flat-bottom tissue culture plates at a density of 15,000 to 20,000 cells per well. After approximately 48 hours, the cell monolayers were rinsed with Hank""s balanced salt solution (HBSS) then preincubated with approximately 150 xcexcl/well of assay buffer (HBSS supplemented with 4 mM MgCl2, 10 mM HEPES, 0.2% BSA [HH]) containing 1 mM 3-isobutyl-1-methylxanthine ([IBMX] Sigma #I-5879) with or without the antagonist compound of interest at 37xc2x0 C. After 20 minutes the 1 mM IBMX-HH assay buffer (xc2x1antagonist compound) was removed and replaced with assay buffer containing 1.5 xcexcM forskolin (Sigma #F-6886) and various concentrations of NPY in the presence or absence of one concentration of the antagonist compound of interest. At the end of 10 minutes, the media were removed and the cell monolayers treated with 75 xcexcl ethanol. The tissue culture plates were agitated on a platform shaker for 15 minutes, after which the plates were transferred to a warm water bath in order to evaporate the ethanol. Upon bringing all wells to dryness, the cell residues were resolubilized with 250 xcexcl FlashPlate assay buffer. The amount of cAMP in each well was quantified using the [125I]-cAMP FlashPlate kit (NEN #SMP-001) and according to the protocol provided by the manufacturer. Data were expressed as either pmol cAMP/ml or as percent of control. All data points were determined in triplicate and EC50""s (nM) were calculated using a nonlinear (sigmoidal) regression equation (GraphPad Prism(trademark)). The KB of the antagonist compound was estimated using the following formula:
KB=[B]/(1xe2x88x92{[Axe2x80x2]/[A]})
where
[A] is the EC50 of the agonist (NPY) in the absence of antagonist,
[Axe2x80x2] is the EC50 of the agonist (NPY) in the presence of antagonist,
and [B] is the concentration of the antagonist.
Human NPY Y5 receptors were expressed in CHO cells. Binding assays were performed in 50 mM HEPES, pH 7.2, 2.5 mM CaCl2, 1 mM MgCl2 and 0.1% BSA containing 5-10 xcexcg of membrane protein and 0.1 nM 125I-peptide YY in a total volume of 200 xcexcl. Non-specific binding was determined in the presence of 1 uM NPY. The reaction mixtures were incubated for 90 minutes at room temperature, then filtered through Millipore MAFC glass fiber filter plates which had been pre-soaked in 0.5% polyethyleneimine. The filters were washed with phosphate-buffered saline, and radioactivity was measured in a Packard TopCount scintillation counter.
For the compounds of this invention, a range of neuropeptide Y5 receptor binding activity from about 0.5 nM to about 1000 nM was observed. Compounds of this invention preferably have a binding activity in the range of about 0.5 nM to 500 nM, more preferably about 0.5 to 100 nM, and most preferably about 0.5 to 10 nM.
Neuropeptide Y Y5 receptor binding activity results for representative compounds of the invention are as follows:
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington""s Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably from about 0.01 mg to about 250 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day, in two to four divided doses.